Abstract
BackgroundNasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC.MethodsWestern blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo.ResultsWe found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance.ConclusionOur data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.
Highlights
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck
We found ER resident protein 44 (ERp44) was highly expressed in Endoplasmic reticulum (ER)-stressed tissues and could reduce cisplatin sensitivity by influencing cell apoptosis and pyroptosis
ERp44 was highly expressed in ER-stressed tissues First of all, we measured the expression of Endoplasmic reticulum stress (ERS)-related marker Glucose-Regulated Protein 78 (GRP78) in NPC
Summary
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. Nasopharyngeal carcinoma (NPC), characterized by its unique distribution, is prevalent in east and southeast Asia [1]. Concurrent chemoradiotherapy has been the standard treatment for locoregionally advanced NPC and could improve patients’ survival [4]. Resistance to chemotherapy is still a major problem for treatment failure [5]. NPC patients are sensitive to chemotherapy in the initial but they might acquire resistance, which will cause the failure of treatment [6]. As cisplatin is commonly a first choice for chemotherapy, determining the mechanism contributing to cisplatin resistance will help us improve treatment efficiency
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